Methods for treating hyperuricemia in patients with gout using halofenate or halogenic acid and a second urate-lowering agent

ABSTRACT

Disclosed herein are pharmaceutical compositions, methods and kits for lowering the serum uric acid level of a subject and for the treatment of a condition associated with elevated serum uric acid levels comprising administering a composition comprising a first urate-lowering agent and a second urate-lowering agent. In some aspects the first urate-lowering agent is (−)-halofenate, (−)-halofenic acid, or a pharmaceutically acceptable salts thereof. In some aspects the second urate-lowering agent is an inhibitor of uric acid production, a uricosuric agent, a uricase, or a pharmaceutically acceptable salt thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application No.61/555,920, filed on Nov. 4, 2011, the complete disclosure of which isincorporated by reference herein.

BACKGROUND

Conditions associated with elevated serum uric acid levels(hyperuricemia) include disorders of urate crystal deposition such asgout arthropathy and tophi, urolithiasis (urinary tract stones), uratenephropathy, as well as the sequelae of these disorders. Hyperuricemiais associated with an increased risk of developing gout arthropathy, andthe risk of gout increases with the degree and duration of thehyperuricemia. In addition to gout arthropathy, chronic hyperuricemiamay lead to the deposition of uric acid crystals in the urinary tract,renal parenchyma, and soft tissues, resulting in urolithiasis, uratenephropathy with chronic kidney disease, and soft tissue tophi,respectively. Because of limitations and disadvantages of current uricacid lowering agents, more effective methods, compositions and therapiesto lower uric acid are needed.

SUMMARY

In one embodiment, the present application describes methods of loweringthe serum uric acid level of a subject with hyperuricemia, the methodcomprising administering to the subject a first urate-lowering agent anda second urate-lowering agent, wherein the first urate-lowering agent isa compound of Formula (I)

wherein R is selected from the group consisting of hydroxy, loweraralkoxy, di-lower alkylamino-lower alkoxy, lower alkanamido-loweralkoxy, benzamido-lower alkoxy, ureido-lower alkoxy, N′-loweralkyl-ureido-lower alkoxy, carbamoyl-lower alkoxy,halophenoxy-substituted lower alkoxy, carbamoyl-substituted phenoxy,carbonyl-lower alkylamino, N,N-di-lower alkylamino-lower alkylamino,halo-substituted lower alkylamino, hydroxyl-substituted loweralkylamino, lower alkanolyloxy-substituted lower alkylamino, ureido, andlower alkoxy carbonylamino; and each X is independently a halogen; or apharmaceutically acceptable salt thereof.

Also disclosed are methods of treating a subject having a conditionassociated with hyperuricemia, the method comprising administering tothe subject a first urate-lowering agent and a second urate-loweringagent, wherein the first urate-lowering agent is a compound of Formula(I). Also disclosed are methods of treating hyperuricemia in a subjectwith gout comprising administering to the subject a compositioncomprising a first urate-lowering agent and a second urate-loweringagent, wherein the first urate-lowering agent is a compound of Formula(I).

Also disclosed are compositions and kits comprising a firsturate-lowering agent and a second urate-lowering agent, wherein thefirst urate-lowering agent is a compound of Formula (I).

In some aspects, the compound of Formula (I) is (−)-halofenate,(−)-halofenic acid, or a pharmaceutically acceptable salt thereof. Insome aspects, the second urate-lowering agent is a xanthine oxidaseinhibitor, an inhibitor of uric acid production, a uricosuric agent or auricase. In some aspects, the second urate-lowering agent is allopurinolor febuxostat. Other aspects are provided below.

Currently available uric acid lowering agents and other therapeuticagents in development have limitations in their ability to lower serumuric acid to a desirable level, and their use may be limited by variousadverse side effects or toxicities. For example, certain agentsincluding allopurinol and febuxostat, when used as the onlyurate-lowering agent to treat hyperurecimia and at commonly prescribeddoses, often fail to reach the common therapeutic target of serum uricacid levels of 6 mg/dL or less. Advantages of the compositions, methods,and kits disclosed herein over currently available uric acid loweringagents at commonly prescribed doses and treatment methods using suchagents may include improved therapeutic benefits; an additive orover-additive effect as compared to the effects of single-agenttherapies; beneficial effects on other conditions associated withhyperuricemia and urate crystal deposition; and provoking fewer or lessintense side effects. In some aspects, the synergistic effect allowsdose reduction or dosing interval extension relative to a currentlyavailable uric acid lowering agent taken individually at prescribeddoses.

DETAILED DESCRIPTION

As utilized in accordance with the present disclosure, the followingterms, unless otherwise indicated, shall be understood to have thefollowing meanings:

“About” when qualifying a number, refers to a range of plus or minus tenpercent of that value or number, unless indicated otherwise. Withoutlimiting the application of the doctrine of equivalents as to the scopeof the claims, each number should be construed in light of such factorsas the number of reported significant digits and the manner or method(e.g. instrumentation, sample preparation, etc.) used to obtain thatnumber.

“Administering” or “administration” refers to the act of giving a drug,prodrug, or therapeutic agent to a subject. Exemplary routes ofadministration are discussed below.

“Acute gout” refers to gout present in a subject with at least one goutysymptom (e.g., podagra or other gouty arthritis, gout flare, goutyattack).

“Arhalofenate” refers to (−)-halofenate, i.e.(−)-(R)-(4-chloro-phenyl)-(3-trifluoromethyl-phenoxy)-acetic acid2-acetylamino-ethyl ester.

“Chronic gout” refers to gout present in a subject having recurrent orprolonged gout flares, tophus formation, chronic inflammatory arthritis,or joint deterioration associated with gout, and includes the periodsfollowing recovery from acute gout and between acute gout attacks (i.e.intercritical gout).

“Composition” or, interchangeably, “formulation” refers to a preparationthat contains a mixture of various excipients and key ingredients thatprovide a relatively stable, desirable, and useful form of a compound ordrug.

The prefixes “d” and “l” or (+) and (−) are employed to designate thesign of rotation of plane-polarized light by the compound, with (+) ord-meaning that the compound is “dextrorotatory” and with (−) orl-meaning that the compound is “levorotatory”. For a given chemicalstructure, these isomers or “optical isomers” are identical except thatthey are mirror images of one another. In describing an optically activecompound, the prefixes R and S are used to denote the absoluteconfiguration of the molecule about its chiral center(s). There is nocorrelation between the nomenclature for the absolute stereochemistryand for the rotation of an enantiomer (i.e., the R-isomer can also bethe l-isomer). A specific optical isomer can also be referred to as an“enantiomer,” and a mixture of such isomers is often called an“enantiomeric” or “racemic” mixture. See, e.g., A. Streitwiesser, & C.H. Heathcock, INTRODUCTION TO ORGANIC CHEMISTRY, 2^(nd) Edition, Chapter7 (MacMillan Publishing Co., U.S.A. 1981). The optical rotation [α]_(D)of (−)-halofenate was measured in methyl alcohol.

“Elevated serum uric acid level” refers to a serum uric acid levelgreater than normal and, in patients with gout, generally refers to aserum uric acid level greater than or equal to about 6 mg/dL. In someinstances, elevated serum uric acid levels are above the mean level in agiven population, such as those of a particular gender or age.

“Effective amount” refers to an amount required (i) at least partly toattain the desired response in a subject; (ii) to delay or to preventthe onset of a particular condition being treated in a subject; or (iii)or to inhibit or to prevent the progression of a particular conditionbeing treated in a subject. The effective amount for a particularsubject varies depending upon the health and physical condition of thesubject to be treated, the taxonomic group of individual to be treated,the degree of protection desired, the formulation of the composition,the assessment of the medical situation, and other relevant factors. Itis expected that the amount will fall in a relatively broad range thatcan be determined through routine trials.

“First urate-lowering agent” refers to a compound of any of Formula (I),(II), (III) or (IV) or a therapeutically acceptable salt or prodrugthereof.

“Gout” refers to a group of disorders or symptoms most often associatedwith the buildup of uric acid due to an overproduction of uric acid or areduced ability of the kidney to excrete uric acid. Gout is oftencharacterized by the deposition of urate crystals (uric acid or saltsthereof, e.g. monosodium urate) in the joints (gouty arthropathy) orsoft tissue (tophi). “Gout” as used herein includes acute gout, chronicgout, moderate gout, refractory gout and severe gout.

“Gout-associated inflammation” refers to local or systemic inflammationdue to immune responses to the deposition of urate crystals.

“Halofenate” refers to the compound of Formula (III), i.e.(4-chlorophenyl)-(3-trifluoromethylphenoxy)-acetic acid2-acetylaminoethyl ester (also referred to as the 2-acetamidoethyl esterof 4-chlorophenyl-(3-trifluoromethylphenoxy)-acetic acid. The termhalofenate and the corresponding chemical names include both the (+) and(−) enantiomer of compounds of Formula (III) as well as mixturesthereof, unless otherwise specified.

“Halofenic acid” and “CPTA” refer to the compound of Formula (IV), i.e.4-chlorophenyl-(3-trifluoromethylphenoxy)-acetic acid [also referred toas 2-(4-chlorophenyl)-2-(3-(trifluoromethyl)phenoxy)acetic acid] as wellas its pharmaceutically acceptable salts. The term halofenic acid andthe corresponding chemical names include both the (+) and (−) enantiomerof compounds of Formula (II) as well as mixtures thereof, unlessotherwise specified.

“Hyperuricemia” refers to an elevated serum uric acid level (see above).

“Lower,” when used to describe chemical substituents of compounds ofFormulae (I) and (II) such as lower aralkoxy, di-lower alkylamino-loweralkoxy, lower alkanamido, lower alkoxy, benzamido-lower alkoxy,ureido-lower alkoxy, N′-lower alkyl-ureido-lower alkoxy, carbamoyl-loweralkoxy, halophenoxy substituted lower alkoxy, carbonyl-lower alkylamino,N,N-di-lower alkylamino-lower alkylamino, halo substituted loweralkylamino, hydroxy substituted lower alkylamino, lower alkanolyloxysubstituted lower alkylamino, lower alkoxycarbonylamino, phenyl-loweralkyl, lower alkanamido-lower alkyl, and benzamido-lower alkyl refers togroups having from one to six carbon atoms. For example, “lower alkoxy”means C₁₋₆alkoxy.

“Moderate gout” refers to gout present in a subject having at least twogout flares in the past 12 months.

“Pharmaceutically acceptable” refers to that which is useful inpreparing a pharmaceutical composition that is generally safe,non-toxic, and neither biologically nor otherwise undesirable, andincludes that which is acceptable for veterinary or human pharmaceuticaluse.

“Pharmaceutically acceptable salt” includes pharmaceutically acceptableacid addition salts and pharmaceutically acceptable base addition saltsand includes both solvated and unsolvated forms. Representativenon-limiting lists of pharmaceutically acceptable salts can be found inS. M. Berge et al., J. Pharma Sci., 66(1), 1-19 (1977), and Remington:The Science and Practice of Pharmacy, R. Hendrickson, ed., 21st edition,Lippincott, Williams & Wilkins, Philadelphia, Pa., (2005), at p. 732,Table 38-5, both of which are hereby incorporated by reference herein.

“Pharmaceutically acceptable acid addition salt” refers to salts formedwith inorganic acids such as hydrochloric acid, hydrobromic acid,sulfuric acid, nitric acid, phosphoric acid and the like, and organicacids such as acetic acid, trifluoroacetic acid, propionic acid,glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid,succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid,cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,p-toluenesulfonic acid, salicylic acid, and the like.

“Pharmaceutically acceptable base addition salt” refers to saltsprepared from the addition of an inorganic base or an organic base tothe free acid. Salts derived from inorganic bases include, but are notlimited to, the sodium, potassium, lithium, ammonium, calcium,magnesium, iron, zinc, copper, manganese, aluminum salts and the like.Salts derived from organic bases include, but are not limited to, saltsof primary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines and basic ionexchange resins, such as isopropylamine, trimethylamine, diethylamine,triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol,2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine,caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine,glucosamine, methylglucamine, theobromine, purines, piperazine,piperidine, N-ethylpiperidine, polyamine resins and the like.

“Refractory gout” refers to gout in patients who are unresponsive orpoorly responsive, or have experienced or are at an increased risk ofexperiencing an adverse event, after being administered either (1) oneor more second urate-lowering agents but not a first urate-loweringagent or (2) a first-urate lowering agent but not a secondurate-lowering agent. The terms “unresponsive” and “poorly responsive”in this context include (1) no or insignificant lowering of serum uricacid, (2) failure to reach a target serum uric acid level (e.g. asdetermined by a physician or other medical practitioner), and (3) thepersistence of one or more gouty conditions or symptoms such as goutflares, gouty tophus, gouty arthritis, or other associated conditionsregardless of any lowering of serum uric acid levels.

“Second urate-lowering agent” refers to a therapeutic agent that lowersserum uric acid levels that is not a first urate-lowering agent. Secondurate-lowering agents include currently available agents (i.e. an agentapproved by the FDA or other appropriate regulatory authority as of thefiling date of this application) that lower serum uric acid, as well ascompounds currently in development or under regulatory review. Examplesof second urate-lowering agents are provided below.

“Subject” and “patient” refer to animals such as mammals, includinghumans, other primates, domesticated animals (e.g. dogs, cats), farmanimals (e.g. horses, cattle, goats, sheep, pigs), rats and mice.

“Severe gout” refers to gout present in a subject having tophaceousdeposits in the joints, skin, or kidneys resulting in chronic arthritis,joint destruction, subcutaneous tophi, or kidney dysfunction, and, insome cases, with subsequent deformity and/or disability.

“Substantially free from” when used in reference to (−)-halofenate or(−)-halofenic acid (or a salt thereof) being substantially free from thecorresponding (+) enantiomer (i.e. (+)-halofenate, (+)-halofenic acid,or a salt thereof) refers to a composition containing a high proportionof a compound's (−) enantiomer in relation to the (+) enantiomer. In oneembodiment, the term means that by weight, the compound included in thecomposition is at least 85% (−) enantiomer and at most 15% (+)enantiomer. In one embodiment, the term means that by weight, thecompound included in the composition is at least 90% (−) enantiomer andat most 10% (+) enantiomer. In other embodiments, the term means that byweight, the compound included in the composition is at least 91% (−)enantiomer and at most 9% (+) enantiomer, at least 92% (−) enantiomerand at most 8% (+) enantiomer, at least 93% (−) enantiomer and at most7% (+) enantiomer, at least 94% (−) enantiomer and at most 6% (+)enantiomer, at least 95% (−) enantiomer and at most 5% (+) enantiomer,at least 96% (−) enantiomer and at most 4% (+) enantiomer, at least 97%(−) enantiomer and at most 3% (+) enantiomer, at least 98% (−)enantiomer and at most 2% (+) enantiomer, or at least 99% (−) enantiomeror greater than 99% (−) enantiomer. Other percentages of the (−) and (+)enantiomers may also be provided. These percentages are based upon theamount of the enantiomer relative to the total amount of bothenantiomers of the compound in the composition.

“Therapeutically effective dose,” “therapeutically effective amount,”or, interchangeably, “pharmacologically acceptable dose” and“pharmacologically acceptable amount” mean that a sufficient amount of atherapeutic agent, therapeutic agents, or metabolites thereof will bepresent in order to achieve a desired result, e.g., lowering uric acidlevels to a target goal or treating gout in its various forms ortreating conditions associated with hyperuricemia.

“Treatment” and “treating” of a disease, disorder, condition or symptomrefer to (1) preventing or reducing the risk of developing the disease,disorder or condition, i.e., causing the clinical symptoms of thedisease, disorder or condition not to develop in a subject who may beexposed to or predisposed to the disease, disorder or condition but whodoes not yet experience or display symptoms of the disease, disorder orcondition (i.e. prophylaxis); (2) inhibiting the disease, disorder orcondition, i.e., arresting or reducing the development of the disease,disorder or condition or its clinical symptoms; and (3) relieving thedisease, disorder or condition, i.e., causing regression, reversal, oramelioration of the disease, disorder or condition or reducing thenumber, frequency, duration or severity of its clinical symptoms. Theterm “management” may be used synonymously.

“Urate” refers to uric acid (7,9-dihydro-1H-purine-2,6,8(3H)-trione) andions and salts thereof.

This application describes compositions, kits and methods for thetreatment of hyperuricemia, that is, for lowering serum uric acidlevels. One aspect of the current disclosure relates to a compositioncomprising a first urate-lowering agent and a second urate-loweringagent, wherein said first urate-lowering agent is a compound of Formula(I)

wherein R is selected from the group consisting of a hydroxy, loweraralkoxy, di-lower alkylamino-lower alkoxy, lower alkanamido-loweralkoxy, benzamido-lower alkoxy, ureido-lower alkoxy, N′-loweralkyl-ureido-lower alkoxy, carbamoyl-lower alkoxy, halophenoxysubstituted lower alkoxy, carbamoyl substituted phenoxy, carbonyl-loweralkylamino, N,N-di-lower alkylamino-lower alkylamino, halo substitutedlower alkylamino, hydroxy substituted lower alkylamino, loweralkanolyloxy substituted lower alkylamino, ureido, and loweralkoxycarbonylamino; and each X is independently a halogen; or apharmaceutically acceptable salt thereof.

In certain aspects, the first urate-lowering agent is a compound ofFormula (II)

wherein R² is selected from the group consisting of phenyl-lower alkyl,lower alkanamido-lower alkyl, and benzamido-lower alkyl; and each X isindependently a halogen, or a pharmaceutically acceptable salt thereof.

In other aspects, the first urate-lowering agent is a compound ofFormula (III), also referred to as halofenate

or a pharmaceutically acceptable salt thereof.

In other aspects, the first urate-lowering agent is a compound ofFormula (IV), also referred to as halofenic acid

or a pharmaceutically acceptable salt thereof.

It should also be noted that any carbon atom with unsatisfied valencesin the formulae and examples herein is assumed to have the hydrogen atomto satisfy the valences.

In certain embodiments the compound is a compound that generates thecompound of Formula (IV) or a pharmaceutically acceptable salt thereofvia a chemical reaction after being administered, as discussed in moredetail below.

Another aspect provides for methods of treating a condition associatedwith an elevated serum uric acid level comprising administering to asubject in need thereof a pharmaceutical composition comprising a firsturate-lowering agent, wherein said first urate-lowering agent is acompound of Formula (I), (II), (III) or (IV) or a pharmaceuticallyacceptable salt thereof; and a second urate-lowering agent. Anotheraspect provides a method of lowering the serum uric acid level in asubject comprising administering to a subject in need thereof apharmaceutical composition comprising a first urate-lowering agent,wherein said first urate-lowering agent is a compound of Formula (I),(II), (III) or (IV) or a pharmaceutically acceptable salt thereof; and asecond urate-lowering agent.

In certain embodiments, the first urate-lowering agent is (−)-halofenate(i.e. (−)-(R)-(4-chloro-phenyl)-(3-trifluoromethyl-phenoxy)-acetic acid2-acetylamino-ethyl ester, also referred to as arhalofenate). In otherembodiments, the first urate-lowering agent is (−)-halofenic acid (i.e.(−)-4-chlorophenyl-(3-trifluoromethylphenoxy) acetic acid) or apharmaceutically acceptable salt thereof. In certain embodiments, the(−)-halofenate, (−)-halofenic acid, or pharmaceutically acceptable saltthereof is substantially free from the corresponding (+) enantiomer.

The enantiomers (stereoisomers) of compounds of Formula (I), (II), (III)or (IV) and pharmaceutically acceptable salt thereof can be prepared byusing reactants or reagents or catalysts in their single enantiomericform in the process wherever possible or by resolving the mixture ofstereoisomers by conventional methods including use of microbialresolution, resolving the diastereomeric salts formed with chiral acidsor chiral bases and chromatography using chiral supports. See, also U.S.Pat. No. 7,199,259 (Daugs), U.S. Pat. Nos. 6,646,004; 6,624,194;6,613,802; and 6,262,118 (each to Luskey et al.), U.S. Pat. No.7,714,131 (Zhu et al.), U.S. Pat. No. 7,432,394 (Cheng et al.) and U.S.Publication No. 2010/0093854 (Broggini et al.) each of which areincorporated herein by reference in their entireties.

The chemical synthesis of racemic mixtures of (3-trihalomethylphenoxy)(4-halophenyl) acetic acid derivatives can also be performed by themethods described in U.S. Pat. No. 3,517,050, the teachings of which areincorporated herein by reference. The individual enantiomers can beobtained by resolution of the racemic mixture of enantiomers usingconventional means known to and used by those of skill in the art. See,e.g., Jaques, J., et al., in Enantiomers, Racemates, and Resolutions,John Wiley and Sons, New York (1981). Other standard methods ofresolution known to those skilled in the art, including but not limitedto, simple crystallization and chromatographic resolution, can also beused (see, e.g., Stereochemistry of Carbon Compounds (1962) E. L. Eliel,McGraw Hill; J. Lochmuller, Chromatography, 113, 283-302 (1975)).Additionally, halofenate, halofenic acid, or a pharmaceuticallyacceptable salt thereof, i.e., the optically pure isomers, can beprepared from the racemic mixture by enzymatic biocatalytic resolution.Enzymatic biocatalytic resolution has been generally describedpreviously (see, e.g., U.S. Pat. Nos. 5,057,427 and 5,077,217, thedisclosures of which are incorporated herein by reference). Othergeneric methods of obtaining enantiomers include stereospecificsynthesis (see, e.g., A. J. Li et al., Pharm. Sci. 86, 1073-77 (1997).

One embodiment provides a composition comprising a pharmaceuticallyacceptable salt of halofenate or halofenic acid. The neutral forms ofthe therapeutic agents may be regenerated by contacting the salt with abase or acid and isolating the parent therapeutic agent in theconventional manner. The parent form of the therapeutic agent differsfrom the various salt forms in certain physical properties, such assolubility in polar solvents, but otherwise the salts are equivalent tothe parent form.

The second urate-lowering agent may be any other agent (i.e. not a firsturate-lowering agent, as defined herein) that lowers serum uric acidlevels. These second urate-lowering agents include inhibitors of uricacid production (e.g. xanthine oxidase inhibitors and purine nucleosidephosphorylase inhibitors), uricosuric agents and uricases.

For example, in some embodiments, the second urate-lowering agent is axanthine oxidase inhibitor. Xanthine oxidase inhibitors lower the amountof urate in blood by decreasing the synthesis of uric acid. Xanthineoxidase is involved in purine metabolism and inhibiting the enzymereduces uric acid levels. Xanthine oxidase inhibitors include, but arenot limited to: allopurinol, febuxostat, oxypurinol, tisopurine, aninositol and propolis. In some embodiments, the xanthine oxidaseinhibitor is allopurinol, febuxostat, oxypurinol, tisopurine, inositol,phytic acid, myo-inositiol, kaempferol, myricetin, and quercetin.Allopurinol (1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one), a xanthineoxidase inhibitor, is the current first line standard of care forlowering urate levels. Another xanthine oxidase inhibitor, febuxostat(2-(3-cyano-4-isobutoxyphenyl)-4-methyl-1,3-thiazole-5-carboxylic acid),was approved for treatment of gout in February 2009. In one embodiment,halofenate, halofenic acid or a pharmaceutically acceptable saltthereof, is administered before, concurrently or subsequent toadministration of allopurinol. In one embodiment, halofenate, halofenicacid or a pharmaceutically acceptable salt thereof is administeredbefore, concurrently or subsequent to administration of febuxostat.

In other embodiments, the second urate-lowering agent is a purinenucleoside phosphorylase (PNP) inhibitor. Purine nucleosidephosphorylase inhibitors represent a relatively new approach to loweringserum uric acid levels in patient with hyperuricemia, gout, and relatedconditions. In some embodiments, the PNP inhibitor is forodesine(BCX1777) (BioCryst Pharmaceuticals, Inc.). In other embodiments, thePNP inhibitor is ulodesine (BCX4208;7-(((3R,4R)-3-hydroxy-4-(hydroxymethyl)pyrrolidin-1-yl)methyl)-3H-pyrrolo[3,2-d]pyrimidin-4(5H)-one)(BioCryst Pharmaceuticals, Inc.). Ulodesine monotherapy administered at40, 80, 120, 160 and 240 mg/day has been shown to rapidly andsignificantly reduced serum uric acid in gout patients.

In some embodiments, the second urate-lowering agent is a uricosuricagent. Uricosuric agents enhance renal excretion of uric acid andgenerally act by lowering the absorption of uric acid from the kidneyproximal tubule back to the blood, e.g., by inhibiting uratetransporters, e.g., SLC22A12. Uricosuric agents include, but are notlimited to, probenecid,2-((5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-yl)thio)aceticacid (RDEA594, lesinurad), potassium4-(2-((5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-yl)thio)acetamido)-3-chlorobenzoate(RDEA806), RDEA684, benzbromarone, sulfinpyrazone, amlodipine,atorvastatin, fenofibrate, guaifenesin, losartan, adrenocorticotropichormone, and cortisone. Probenecid is the most commonly used uricosuricagent in the U.S. and may be given in combination with allopurinol tosome gout patients. Benzbromarone and sulfinpyrazone are also used asfirst line uricosuric agents. Guaifenesin, losartan, atorvastatin,amlodipine, adrenocorticotropic hormone (ACTH or corticotropin),fenofibrate, levotofisopam and cortisone also have uricosuric effects.In one embodiment, a first urate-lowering agent (e.g. (−)-halofenate,(−)-halofenic acid or a pharmaceutically acceptable salt thereof) isadministered before, concurrently or subsequent to administration of auricosuric agent. In one embodiment, a first urate-lowering agent (e.g.(−)-halofenate, (−)-halofenic acid or a pharmaceutically acceptable saltthereof) is administered before, concurrently or subsequent toadministration of probenecid, benzbromarone or sulfinpyrazone.

In some embodiments, the second urate-lowering agent is a uricaseenzyme, or a fragment or pegylated derivative thereof. Uricase or urateoxidase enzymes are found in many mammals but not in humans. They canlower uric acid levels by converting uric acid into allantoin, a benignend metabolite which is easily excreted in the urine. Uricase enzymesinclude, but are not limited to, rasburicase or a pegylated uricaseenzyme (PEG-uricase). In some embodiments, the pegylated uricase enzymeis Krystexxa® (PURICASE®; pegloticase) (Savient Pharmaceuticals, Inc.)which is approved in the U.S. for the treatment of chronic gout in adultpatients refractory to conventional therapy.

The present disclosure also provides for methods of treating one or moreconditions associated with an elevated serum uric acid level, i.e.hyperuricemia, the methods comprising administering to a subject in needthereof a pharmaceutical composition comprising a first urate-loweringagent, wherein said first urate-lowering agent is a compound of Formulae(I), (II), (III) or (IV) or a pharmaceutically acceptable salt thereof;and a second urate-lowering agent. Conditions associated withhyperuricemia include, but are not limited to gout; acute gout; chronicgout; moderate gout; refractory gout; severe gout; deposition of uricacid crystals in the urinary tract, renal parenchyma, soft tissues,joints, cartilage or bones; urolithiasis; urate nephropathy; tophi;podagra; acute inflammatory gouty arthritis; joint destruction; urinarytract infections; renal impairment; chronic kidney disease; kidneystones; local inflammation; systemic inflammation; immune-relateddisorders; cardiovascular disease including peripheral vascular disease,coronary artery disease and cerebrovascular disease; insulin resistance;diabetes; fatty liver disease; dementia including vascular dementia;dyslipidemia; preeclampsia; hypertension; obesity; muscle spasm;localized swelling; pain including joint pain, muscle fatigue;tumor-lysis syndrome; and stress feelings. Additional conditionsassociated with hyperuricemia include, but are not limited to,Lesch-Nyhan syndrome, Kelley-Seegmiller syndrome and related conditions.

A variety of factors increase the risk that a patient will have gout orwill experience one or more of its symptoms. In addition tohyperuricemia, these factors include obesity, diabetes, chronic kidneyfailure, hypertension, use of diuretic drugs and certain other drugs(e.g. salicylates, pyrazinamide, ethambutol, nicotinic acid,cyclosporin, 2-ethylamino-1,3,4-thiadiazole, fructose and cytotoxicagents), overeating or fasting, a high purine diet, a high fructosediet, exposure to lead, consumption of red meat and protein, alcoholintake, and injury or recent surgery. Acute gout can be precipitated byperioperative ketosis in surgical patients, reduced body temperature,e.g., while sleeping, and by dehydration, e.g., by use of diureticdrugs. Genetic risk factors for gout and hyperuricemia have also beenidentified.

In various embodiments, the methods described herein may be used totreat any of the aforementioned conditions or disorders. That is, in oneembodiment, the condition associated with an elevated serum uric acidlevel is gout. In some embodiments, the subject has acute gout. In someembodiments, the subject has chronic gout. In some embodiments thesubject has moderate gout. In some embodiments the subject hasrefractory gout. For example, in some embodiments, a subject has beenadministered a second urate-lowering agent (e.g. allopurinol,febuxostat, probenecid, Krystexxa®, etc.) and has not been administereda first urate-lowering agent, and has been deemed to be poorlyresponsive or unresponsive as defined above (e.g. has failed to reach atarget urate level (e.g. 6.0 mg/dL)). In some embodiments the subjecthas severe gout. For example, one method provides for the management ofhyperuricemia in a subject with gout. Certain methods provide for thetreatment or management of hyperuricemia in a subject with goutcomprising administering a pharmaceutical composition comprising a firsturate-lowering agent and a second urate-lowering agent. In someembodiments the first urate-lowering agent is (−)-halofenate,(−)-halofenic acid or a pharmaceutically acceptable salt thereof. Incertain embodiments, the treatment can be for about four weeks orlonger, for about one month or longer, for about 12 weeks or longer, forabout three months or longer, for about six months or longer, for aboutone year or longer, for about two years or longer, for about five yearsor longer, for about 10 years or longer. In certain embodiments thetreatment can be indefinite, e.g. for the remainder of the lifetime ofthe subject. In certain embodiments the second urate-lowering agent isselected from the group consisting of a uric acid synthesis inhibitor, auricase, and a uricosuric agent, and pharmaceutically acceptable saltsthereof. In certain embodiments the second agent may be allopurinol orfebuxostat.

In various embodiments the methods comprise treating gout. In someembodiments, the methods comprise treating gout by preventing goutflares. In another embodiment the method comprises reducing the number,frequency, duration or severity of one of more gout flares. In anotherembodiment the method comprises preventing, reducing or reversing uricacid crystal formation. In some embodiments of the methods for treatinguric acid crystal formation, the uric acid crystal formation is in oneor more of the joints, under skin, and kidney. In some embodiments, theformations include tophaceous deposits. In some embodiments, the subjecthas uric acid crystal formation determined by aspiration of tophi or byaspiration of synovial fluid of an inflamed joint. In another embodimentthe method comprises reducing uric acid burden. In another embodimentthe method comprises reducing the size or number of tophi. The size ornumber of tophi may be assessed by known methods, for example, use of CTscans.

This application also provides methods of lowering the serum uric acidlevel, treating a subject having a condition associated with an elevatedserum uric acid level, and treating hyperuricemia in a subject withgout, in subjects with refractory gout. In certain embodiments, thesubject is refractory to allopurinol,2-((5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-yl)thio)aceticacid (RDEA594, lesinurad),2-(3-cyano-4-isobutoxyphenyl)-4-methyl-1,3-thiazole-5-carboxylic acid(febuxostat), or ulodesine (BCX4208). In some embodiments the subject isrefractory to allopurinol. For example, in one embodiment, the subjectis refractory to allopurinol administered at from 100 mg/day to 800mg/day (e.g. from 100 mg/day to 300 mg/day) for about one month orlonger, about three months or longer, about one year or longer, etc. Insome embodiments the subject is refractory to febuxostat. For example,in one embodiment the subject is refractory to febuxostat administeredat from 40 mg/day to 120 mg/day for about one month or longer, aboutthree months or longer, about one year or longer, etc. In certainembodiments the subject has mild or moderate chronic kidney disease(CKD2-3). In other embodiments the subject has severe chronic kidneydisease (CKD4). In other embodiments, the subject is on aspirin ordiuretic therapy.

It will be recognized by persons with ordinary skill in the art thatpatients with gout or at risk of developing gout may be administeredagents such as non-steroidal anti-inflammatory drugs (NSAIDS),colchicine, steroids, or similar medicaments to treat or manage goutflares. Accordingly, in certain embodiments of the methods describedherein, the subjects may also be administered an agent such as an NSAID,colchicine or a steroid.

The methods described herein may be accomplished by the administrationof a compound that generates the compound of Formula (IV) or a saltthereof via a chemical reaction after being administered. Such compoundsinclude prodrugs of the compound of Formula (IV). Prodrugs of a compoundare prepared by modifying functional groups present in the compound insuch a way that the modifications may be cleaved in vivo to release theparent compound, or an active metabolite. For example, prodrugs includecompounds wherein a hydroxy, amino, or sulfhydryl group in a compound isbonded to any group that may be cleaved in vivo to regenerate the freehydroxyl, amino, or sulfhydryl group, respectively. Certain prodrugs mayincrease the bioavailability of the compounds of the embodiments whensuch compounds are administered to a subject (e.g., by allowing anorally administered compound to be more readily absorbed into the blood)or which enhance delivery of the parent compound to a certain organ ortissue (e.g., kidneys, adipose tissue, liver, muscles or joints)relative to the parent species. Prodrugs of the compound of Formula (IV)include esters, amides, and carbamates (e.g., N,N-dimethylaminocarbonyl)of the hydroxy functional group of the compound of Formula (IV). Thecompounds of Formulae (I), (II) and (III) are non-limiting examples ofprodrugs of the compound of Formula (IV). Further examples of prodrugscan be found in J. Rautio et al. Prodrugs: design and clinicalapplications, Nat. Rev. Drug Discov., 7, 255-270 (2008); Edward B.Roche, ed., Bioreversible Carriers in Drug Design, AmericanPharmaceutical Association and Pergamon Press, (1987); and T. Higuchiand V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of theA.C.S. Symposium Series (1975), each of which are hereby incorporated byreference herein.

In various embodiments, the compositions, methods, and kits describedherein lower serum uric acid levels in a subject by about 5%, about 10%,about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%,about 80%, about 85%, about 90% or more, as compared to serum uric acidlevels in the subject prior to administering the methods describedherein. In various embodiments, serum uric acid levels are decreasedabout 5% to about 50%, decreased by about 25% to about 75%, or decreasedby about 50% to about 99%. Methods to determine serum uric acid levelsare well known in the art and are often measured as part of a standardchemistry panel of blood serum samples.

In some embodiments, the compositions, methods, and kits of the presentdisclosure lower serum uric acid levels in a subject to about 7 mg/dL orless, to about 6.8 mg/dL or less, to about 6 mg/dL or less, to about 5mg/dL or less, to about 4 mg/dL or less, or to about 3 mg/dL or less ascompared to serum uric acid levels in the subject prior to administeringthe methods or compositions described herein. In some embodiments, themethods of the present disclosure lower serum uric acid levels in asubject by 0.1, 0.2, 0.3, 0.4, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0,4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5 or 10.0 mg/dL, orgreater, as compared to serum uric acid levels in the subject prior toadministering the methods or compositions described herein. In furtherembodiments, the methods described herein lower serum uric acid levelsby between 0.1 and 10.0 mg/dL, between 0.5 and 6.0 mg/dL, between 1.0and 4.0 mg/dL or between 1.5 and 2.5 mg/dL. The appropriate serum uricacid level may vary depending on the subject, and may vary for a givensubject over time, depending upon the subject's overall medicalcondition. Similarly, the appropriate serum uric acid level for onegroup of subjects sharing a common medical condition may be differentfrom that which is appropriate for a different group of subjects sharinga different medical condition. Thus, it may be advisable to reduce theserum uric acid level of a given group of subjects to, for example,below about 5 mg/dL, and to reduce the serum uric acid level of adifferent group of subjects to, for example, below about 4 mg/dL. Incertain embodiments, the methods of the present disclosure decrease aserum uric acid level in the subject by an amount sufficient to resultin the disappearance, reduction, amelioration, or the prevention of theonset, of one or more conditions associated with elevated serum uricacid over a certain timeframe, for example about four weeks or longer,about one month or longer, about three months or longer, about one yearor longer, about two years or longer, etc. For example, a method candecrease the serum uric acid level in a subject by an amount sufficientto result in the disappearance or reduction of tophi over about fourweeks or longer, about one month or longer, about three months orlonger, about one year or longer, about two years or longer, etc.

In further embodiments, the methods of the present disclosure compriseadministering a pharmaceutical composition comprising a firsturate-lowering agent and a second therapeutic agent, as describedherein, to a subject whose serum uric acid level is at least about 4mg/dL, at least about 5 mg/dL, at least about 6 mg/dL, at least about6.8 mg/dL, at least about 7 mg/dL, at least about 8 mg/dL, at leastabout 9 mg/dL, at least about 10 mg/dL, or at least about 11 mg/dL.Again, the amount of decrease of serum uric acid level that isappropriate may vary depending on the subject, depending upon thesubject's overall medical condition. Similarly, the amount of decreaseof serum uric acid level that is appropriate for one group of subjectssharing a common medical condition may be different from that which isappropriate for a different group of subjects sharing a differentmedical condition.

The therapeutic agents and combinations thereof disclosed herein arecontemplated to exhibit therapeutic activity when administered in anamount which can depend on the particular case. The variation in amountcan depend, for example, on the subject being treated and the activeingredients chosen. A broad range of doses can be applicable. Dosageregimes may be adjusted to provide the optimum therapeutic response. Forexample, several divided doses may be administered daily, weekly,monthly or other at suitable time intervals or the dose may beproportionally reduced as indicated by the exigencies of the situation.Such dosages are optionally altered depending on a number of variables,not limited to the activity of the one or more active ingredients used,the disease or condition to be treated, the mode of administration, therequirements of the individual subject, the severity of the disease orcondition being treated, and the judgment of the practitioner.

As described throughout, the present disclosure contemplates combinationtherapy and methods of concomitant administration of a first and secondurate-lowering agent (wherein these first and second urate-loweringagents are described above). Combination therapy and concomitantadministration refer to the administration of the two agents (i.e., afirst agent and a second urate-lowering agent, as described above) inany manner in which the pharmacological effects of both are manifestedin the subject at the same time. Thus, such administration does notrequire that a single pharmaceutical composition, the same type offormulation, the same dosage form, or even the same route ofadministration be used for administration of both the first and secondurate-lowering agents, or that the two agents be administered at thesame time. Such administration may be accomplished most conveniently bythe same dosage form and the same route of administration, atsubstantially the same time. For example, a first urate-lowering agent,e.g. halofenate, halofenic acid, or a pharmaceutically acceptable saltthereof, and a second urate-lowering agent, e.g. xanthine oxidaseinhibitor (e.g., allopurinol or febuxostat), can be administered to thehuman subject together in a single oral dosage composition, such as atablet or capsule, or each agent can be administered in separate oraldosage formulations. One advantage with separate formulations is anadded flexibility in dosing, i.e. the dosage of the first and secondurate-lowering agents can be changed independently, quickly, and easily.Where separate dosage formulations are used, the first and secondurate-lowering agents can be administered at essentially the same time(i.e., simultaneously or concurrently), or at separately staggered times(i.e., sequentially).

Depending on factors such as the diagnosis, symptoms, and therapeuticgoals of a particular subject, a wide range of dosages of the first andsecond agent can be contemplated. In various embodiments, the firsturate-lowering agents may be administered from about 10 mg to about 1000mg per day and the second urate-lowering agent may be administered fromabout 10 mg to about 4000 mg per day. For example, halofenate, halofenicacid, or a pharmaceutically acceptable salt thereof may be administeredat about 100 mg/day, about 200 mg/day, about 300 mg/day, about 400mg/day, about 500 mg/day, about 600 mg/day, about 700 mg/day, about 800mg/day, about 900 mg/day, or about 1000 mg/day.

As described above, in certain embodiments the second agent isallopurinol. By way of non-limiting example, the currently recommendeddaily dosage of allopurinol is from 100 mg/day to 800 mg/day inincrements of 100 mg/day. When administered as a second urate-loweringagent as described herein (i.e. when a first urate-lowering agent isalso administered), the dosage range of allopurinol may be within,above, or below the currently recommended daily dosage, as providedabove and as appropriate for the subject being treated. By way ofnon-limiting example, in certain embodiments wherein the firsturate-lowering agent is arhalofenate (i.e. (−)-halofenate) and whereinthe second urate-lowering agent is allopurinol, the following dailydosages may be administered: arhalofenate 100 mg/day, allopurinol 50mg/day; arhalofenate 100 mg/day, allopurinol 100 mg/day; arhalofenate100 mg/day, allopurinol 200 mg/day; arhalofenate 100 mg/day, allopurinol300 mg/day; arhalofenate 100 mg/day, allopurinol 400 mg/day;arhalofenate 100 mg/day, allopurinol 600 mg/day; arhalofenate 100mg/day, allopurinol 800 mg/day; arhalofenate 200 mg/day, allopurinol 50mg/day; arhalofenate 200 mg/day, allopurinol 100 mg/day; arhalofenate200 mg/day, allopurinol 200 mg/day; arhalofenate 200 mg/day, allopurinol300 mg/day; arhalofenate 200 mg/day, allopurinol 400 mg/day;arhalofenate 200 mg/day, allopurinol 600 mg/day; arhalofenate 200mg/day, allopurinol 800 mg/day; arhalofenate 300 mg/day, allopurinol 50mg/day; arhalofenate 300 mg/day, allopurinol 100 mg/day; arhalofenate300 mg/day, allopurinol 200 mg/day; arhalofenate 300 mg/day, allopurinol300 mg/day; arhalofenate 300 mg/day, allopurinol 400 mg/day;arhalofenate 300 mg/day, allopurinol 600 mg/day; arhalofenate 300mg/day, allopurinol 800 mg/day; arhalofenate 400 mg/day, allopurinol 50mg/day; arhalofenate 400 mg/day, allopurinol 100 mg/day; arhalofenate400 mg/day, allopurinol 200 mg/day; arhalofenate 400 mg/day, allopurinol300 mg/day; arhalofenate 400 mg/day, allopurinol 400 mg/day;arhalofenate 400 mg/day, allopurinol 600 mg/day; arhalofenate 400mg/day, allopurinol 800 mg/day; arhalofenate 600 mg/day, allopurinol 50mg/day; arhalofenate 600 mg/day, allopurinol 100 mg/day; arhalofenate600 mg/day, allopurinol 200 mg/day; arhalofenate 600 mg/day, allopurinol300 mg/day; arhalofenate 600 mg/day, allopurinol 400 mg/day;arhalofenate 600 mg/day, allopurinol 600 mg/day; arhalofenate 600mg/day, allopurinol 800 mg/day; arhalofenate 800 mg/day, allopurinol 50mg/day; arhalofenate 800 mg/day, allopurinol 100 mg/day; arhalofenate800 mg/day, allopurinol 200 mg/day; arhalofenate 800 mg/day, allopurinol300 mg/day; arhalofenate 800 mg/day, allopurinol 400 mg/day;arhalofenate 800 mg/day, allopurinol 600 mg/day; arhalofenate 800mg/day, allopurinol 800 mg/day.

Also as described above, in certain embodiments the second agent isfebuxostat. By way of non-limiting example, the currently recommendeddaily dosage of febuxostat is 40 mg/day or 80 mg/day in the UnitedStates, and 10 mg/day, 40 mg/day, 80 mg/day or 120 mg/day in certainother countries. When administered as a second urate-lowering agent asdescribed herein (i.e. when a first urate-lowering agent is alsoadministered), the dosage range of febuxostat may be within, above, orbelow the currently recommended daily dosage, as provided above and asappropriate for the subject being treated. By way of non-limitingexample, in certain embodiments wherein the first urate-lowering agentis arhalofenate (i.e. (−)-halofenate) and wherein the secondurate-lowering agent is febuxostat, the following daily dosages may beadministered: arhalofenate 100 mg/day, febuxostat 10 mg/day;arhalofenate 100 mg/day, febuxostat 40 mg/day; arhalofenate 100 mg/day,febuxostat 80 mg/day; arhalofenate 100 mg/day, febuxostat 120 mg/day;arhalofenate 100 mg/day, febuxostat 240 mg/day; arhalofenate 200 mg/day,febuxostat 10 mg/day; arhalofenate 200 mg/day, febuxostat 40 mg/day;arhalofenate 200 mg/day, febuxostat 80 mg/day; arhalofenate 200 mg/day,febuxostat 120 mg/day; arhalofenate 200 mg/day, febuxostat 240 mg/day;arhalofenate 300 mg/day, febuxostat 10 mg/day; arhalofenate 300 mg/day,febuxostat 40 mg/day; arhalofenate 300 mg/day, febuxostat 80 mg/day;arhalofenate 300 mg/day, febuxostat 120 mg/day; arhalofenate 300 mg/day,febuxostat 240 mg/day; arhalofenate 400 mg/day, febuxostat 10 mg/day;arhalofenate 400 mg/day, febuxostat 40 mg/day; arhalofenate 400 mg/day,febuxostat 80 mg/day; arhalofenate 400 mg/day, febuxostat 120 mg/day;arhalofenate 400 mg/day, febuxostat 240 mg/day; arhalofenate 600 mg/day,febuxostat 10 mg/day; arhalofenate 600 mg/day, febuxostat 40 mg/day;arhalofenate 600 mg/day, febuxostat 80 mg/day; arhalofenate 600 mg/day,febuxostat 120 mg/day; arhalofenate 600 mg/day, febuxostat 240 mg/day;arhalofenate 800 mg/day, febuxostat 10 mg/day; arhalofenate 800 mg/day,febuxostat 40 mg/day; arhalofenate 800 mg/day, febuxostat 80 mg/day;arhalofenate 800 mg/day, febuxostat 120 mg/day; and arhalofenate 800mg/day, febuxostat 240 mg/day.

Other dose ranges within the ranges described for each of the firsturate-lowering agent and the second urate-lowering agent may be readilyenvisaged. One of skill in the art will appreciate that the dose anddosing regimen may be adjusted when therapeutic agents are used incombination. When such combinations are used, the dose of one or more ofthe agents may be reduced to a level below the level required for adesired efficacy when the one or more agents are used alone. Similarly,the dosing regimen may be modified, e.g., to synchronize the dosing ofthe one or more therapeutic agents to facilitate improved patient easeof use and compliance. Alternately, the dosing regimen of the one ormore therapeutic agents can be sequential, e.g., to reduce the combinedload of the agents at a given time. For example, in certain embodiments,the dose of the second urate-lowering agent (e.g. allopurinol,febuxostat, or the other second urate-lowering agents described herein)can be adjusted to a lower level than that currently recommended whenthe first urate-lowering agent is and second urate-lowering agents areadministered.

In certain embodiments, the concomitant administration of a firsturate-lowering agent and a second urate-lowering agent provides anadditive effect or a over-additive effect. As used herein, the term“additive effect” refers to the combined effect of two or morepharmaceutically active agents that is approximately equal to the sum ofthe effect of each agent given alone, and the term “over-additiveeffect” refers to the combined effect of two or more pharmaceuticallyactive agents that is greater than the sum of the effect of each agentgiven alone. For example, in some embodiments, the concomitantadministration of a first urate-lowering agent and a secondurate-lowering agent provides an additive lowering of serum uric acid ina subject. In some embodiments, the concomitant administration of afirst urate-lowering agent and a second urate-lowering agent provides anadditive or over-additive lowering of serum uric acid in a subject. Forexample, the concomitant administration of (−)-halofenate and febuxosatmay provide an additive or over-additive lowering of serum uric acid. Incertain embodiments, the first urate-lowering agent and the secondurate-lowering agent are compatbile. As used herein, the term“compatible” means that no clinically significant adverse drug-druginteraction occurs. By way of non-limiting example, an adverse drug-druginteraction could manifest as a lower plasma concentration of a secondurate-lowering agent or its metabolite when a first urate-lowering agentand a second urate-lowering agent are concomitantly administered ascompared to the corresponding concentration when administered withoutthe other agent and at the same dosage.

Dose titration or dose escalation protocols may be employed to determinethe proper or optimal dose to administer to a subject. For example, dosetitration or escalation studies may select for doses that improveefficacy or tolerability. Dose titration or escalation allows for thegradual adjusting of the dose administered until the desired effect isachieved. Dose titration gradually decreases the dosage administeredwhile dose escalation gradually increases the dose administered. Methodsof dose titration and escalation are well known in the art. As anon-limiting example, a subject may be administered 600 mg/day(−)-halofenate, (−)-halofenic acid, or a pharmaceutically acceptablesalt thereof every day and measured for serum uric acid levels on adaily basis. The dosage may be increased or decreased, for example, on aweekly basis. The subject may be monitored for a period of, for example,2 to 12 weeks to find the desired dose.

In accordance with the compositions, methods and kits described herein,the first urate-lowering agent and second urate-lowering agent may beadministered in any manner in which the pharmacological effects of bothare likely to be manifested in the subject at approximately the sametime. Such administration does not require that a single pharmaceuticalcomposition, the same type of formulation, the same dosage form, or eventhe same route of administration be used for administration of both thefirst and second urate-lowering agents, or that the two agents beadministered at the same time. That is, in various embodiments, thefirst urate-lowering agent and the second urate-lowering agent describedherein may be present in a single dosage form (e.g. a single tablet orcapsule for oral administration), and in other embodiments the firsturate-lowering agent may be present in a first dosage form (e.g. a firsttablet or capsule) and the second urate-lowering agent may be present ina second dosage form (e.g. a second tablet or capsule). The dosage formsmay include the first and second urate-lowering agents in dosesaccording to the examples provided above. A single dosage form (e.g. asingle tablet or capsule) may include a single daily supply of the firstand second urate-lowering agent, or a fraction thereof, e.g. one-half ofa daily supply, one-third a daily supply, one-fourth a daily supply,etc. For example, the pharmaceutical composition described herein can bein a single tablet comprising 600 mg of arhalofenate and 150 mg ofallopurinol. By way of further example, the pharmaceutical compositiondescribed herein can be in a single tablet comprising 800 mg ofarhalofenate and 40 mg of febuxostat. Other dosage forms within thescope of this disclosure may be readily envisaged.

In unit dosage form, the formulation may be divided into unit dosescontaining appropriate quantities of the one or more active ingredients.In some embodiments, the unit dosage is in the form of a packagecontaining discrete quantities of the formulation. Non-limiting examplesinclude packaged tablets or capsules, and powders in vials or ampoules.In some embodiments, aqueous suspension compositions are packaged insingle-dose non-reclosable containers. Alternatively, multiple-dosereclosable containers are used, in which case it is typical to include apreservative in the composition. By way of example only, formulationsfor parenteral injection are presented in unit dosage form, whichinclude, but are not limited to ampoules, or in multi dose containers,with an added preservative. Tablets, troches, pills, capsules and thelike may also contain the components as listed hereafter: a binder suchas gum, acacia, corn starch or gelatin; excipients such as dicalciumphosphate; a disintegrating agent such as corn starch, potato starch,alginic acid and the like; a lubricant such as magnesium stearate; and asweetening agent such as sucrose, lactose or saccharin may be added or aflavoring agent such as peppermint, oil of wintergreen, or cherryflavoring. When the dosage unit form is a capsule, it may contain, inaddition to materials of the above type, a liquid carrier. Various othermaterials may be present as coatings or to otherwise modify the physicalform of the dosage unit. For instance, tablets, pills, or capsules maybe coated with shellac, sugar or both. A syrup or elixir may contain oneor more active ingredients, sucrose as a sweetening agent, methyl andpropylparabens as preservatives, a dye and flavoring such as cherry ororange flavor. In some embodiments, additional ingredients, for example,nonsteroidal anti-inflammatory drugs or colchicine, ingredients fortreating other related indications, or inert substances such asartificial coloring agents are added. Of course, any material used inpreparing any dosage unit form should be pharmaceutically pure andsubstantially non-toxic in the amounts employed. In addition, the one ormore active ingredients may be incorporated into sustained-releasepreparations and formulations as described herein.

The pharmaceutical compositions of the present disclosure may beadministered once daily (QD), twice daily (BID), three times daily (TID)or four times per day (QID). In one embodiment, the pharmaceuticalcomposition of the present disclosure is administered once daily (QD).In another embodiment, the pharmaceutical composition of the presentdisclosure is administered twice daily (BID).

This disclosure also describes articles of manufacture such as kitscomprising a composition comprising a first and second urate-loweringagent (wherein these first and second urate-lowering agents aredescribed above). In some embodiments the first urate-lowering agent inthe kit is (−)-halofenate (i.e. arhalofenate). In some embodiments thesecond urate-lowering agent in the kit is allopurinol. In otherembodiments the second urate-lowering agent in the kit is febuxostat.The kits can include the compositions packaged for distribution and inquantities sufficient to carry out the methods described herein. Kitsmay also include instructions (e.g. a package insert, package label,etc.) for using the kit components in one or more methods describedherein. For example, a kit may comprise dosage forms of a firsturate-lowering agent and a second urate-lowering agent described herein,and instructions for prescribing, administering or otherwise using thedosage forms to lower serum uric acid levels. In some embodiments a kitis for a subject with hyperuricemia or a condition associated withhyperuricemia (e.g., gout) to use in the self-administration of thepharmaceutical composition, wherein the kit comprises a containerhousing a plurality of dosage forms containing a first and secondurate-lowering agent described herein and instructions for carrying outdrug administration therewith. In one embodiment, a kit comprises afirst dosage form comprising halofenate, halofenic acid, or apharmaceutically acceptable salt thereof in one or more of the formsidentified above and at least a second dosage form comprising one ormore of the forms identified above, in quantities sufficient to carryout the methods of the present disclosure. The second dosage form, andany additional dosage forms (e.g., a third, fourth of fifth dosage form)can comprise any active ingredient disclosed herein for the treatment ofa hyperuricemic disorder (e.g., gout). All dosage forms together cancomprise a therapeutically effective amount of each compound for thetreatment of a condition associated with hyperuricemia (e.g., gout). Insome embodiments a kit is for a subject with a condition associated withhyperuricemia (e.g., gout) to use in the self-administration of at leastone oral agent, wherein the kit comprises a container housing aplurality of said oral agents and instructions for carrying out drugadministration therewith.

EXAMPLES Example 1 Clinical Trial

A randomized, double-blind, placebo-controlled study to evaluate thesafety and efficacy of daily oral doses of between 400 to 600 mg ofarhalofenate (i.e., (−)-halofenate) in combination with 300 mg oraldoses of allopurinol was conducted in gout patients with inadequatehypouricemic (uric acid lowering) response to allopurinol alone. Asubset of enrolled patients volunteered to participate in theallopurinol/oxypurinol serial PK sample collection sub-study.

Patients who met the final eligibility criteria were randomized to eachof 3 study arms in the following manner (1:1:1):

-   -   Arhalofenate 400 mg (plus allopurinol 300 mg)    -   Arhalofenate 600 mg (plus allopurinol 300 mg)    -   Placebo (plus allopurinol 300 mg)        The serum uric acid (sUA) levels were assessed at Day 1, prior        to giving blinded study medication, and at Visits Week 2, 3, and        4.

Dose/Route/Regimen:

Colchicine at 0.6 mg was administered once daily orally to patients inall treatment groups starting at Week-3 through the final studyfollow-up visit, as background therapy for prophylaxis of gout flares.Patients in all treatment groups also took allopurinol 300 mg once dailyorally starting at Week-3 during the run-in and continuing through Week4.

The randomized treatment regimens were as follows (Day 1 through Week4):

-   -   Treatment Group #1: Arhalofenate 400 mg (plus allopurinol)    -   Treatment Group #2: Arhalofenate 600 mg (plus allopurinol)    -   Treatment Group #3: Placebo (plus allopurinol)        Safety

The interpretation of the safety and tolerability ofallopurinol-arhalofenate combination treatment was made based on theassessment of safety parameters evaluated throughout the study,including clinical laboratory tests, 12-lead ECGs, vital signs, physicalexamination, concomitant medication review, and treatment emergentadverse events (AEs). The reporting of the safety data was descriptive,and included all patients receiving at least one dose of arhalofenate orallopurinol.

Pharmacodynamics

The effects of each of the three treatment groups were assessed as thechange in sUA from baseline to the end of the treatment period for thefollowing endpoints:

-   -   Percent change in sUA from baseline at Week 4 of treatment    -   The proportion of patients achieving a sUA<6 mg/dL at week 4 of        treatment    -   The proportion of patients achieving a sUA<5 mg/dL at week 4 of        treatment    -   The proportion of patients achieving a sUA<4 mg/dL at week 4 of        treatment

Results:

A total of 100 patients were randomized and received at least one doseof double-blind study medication: 33 received 300 mg allopurinol plusplacebo, 35 received 400 mg arhalofenate plus 300 mg allopurinol, and 32received 600 mg arhalofenate plus 300 mg allopurinol. Patients whoreceived at least one dose of double-blind study medication are includedin the safety analysis.

At Week 4, after four weeks of daily treatment with blinded study drug,the mean percent sUA change from baseline were statistically significantin all treatment groups: −9.5% in Placebo plus Allopurinol 300 mg group(p=0.0090), −16.0% in Arhalofenate 400 mg plus Allopurinol 300 mg group(p<0.0001), and −9.9% in arhalofenate 600 mg plus Allopurinol 300 mggroup (p=0.0037). No statistically significant differences were seenwhen comparing the arhalofenate+allopurinol treated groups withplacebo+allopurinol group.

TABLE 1 Summary and Analysis of Percent Changes from Baseline in UricAcid (mg/dL) at the End of Treatment 400 mg 600 mg Placebo +Arhalofenate + Arhalofenate + Allopurinol Allopurinol Allopurinol (N =31) (N = 34) (N = 30) Baseline¹ n 31 34 30 Mean (SD) 7.1 (1.0) 7.3 (1.1)7.1 (1.1) SEM 0.2 0.2 0.2 Median 6.8 7.1 6.8 Minimum, 6.0, 9.9 6.0, 9.9  6.0 11.2 maximum End of Treatment (LOCF) n 31 34 30 Mean (SD) 6.3(1.1) 6.1 (1.5) 6.4 (1.3) SEM 0.2 0.3 0.2 Median 6.2 5.9 6.0 Minimum,3.9, 8.4  3.4, 10.1 4.3, 8.8 maximum % Change from Baseline Mean (SD)−9.5 (19.0) −16.0 (20.9)   −9.9 (17.1) SEM 3.4 3.6 3.1 Median −8.7 −18.8−8.8 Minimum, −57.6, 27.3   −46.0, 56.5   −46.4, 41.9   maximum P-valuefor within 0.0090² <0.0001³ 0.0037² Group Change P-value for Change fromBaseline⁴ Arhalofenate vs 0.1956 0.9415 placebo 600 mg vs 0.2053 400 mgMean Difference CI (−16.5, 3.4) (−9.6, 8.9) (Treatment − allopurinolalone)

By the End of Treatment (Week 4), 11 patients in the placebo+allopurinol300 mg group, 18 patients in the arhalofenate 400 mg+allopurinol 300 mggroup and 13 patients in the arhalofenate 600 mg+allopurinol 300 mggroup had sUA<6.0 mg/dL; 4 patients in the placebo+allopurinol 300 mggroup, 8 patients in the arhalofenate 400 mg+allopurinol 300 mg groupand 4 patients in the arhalofenate 600 mg+allopurinol 300 mg group hadsUA<5.0 mg/dL; and 1 patients in the placebo+allopurinol 300 mg group,and 1 patients in the arhalofenate 400 mg+allopurinol 300 mg group hadsUA<4.0 mg/dL. No statistically significant differences were seenbetween the arhalofenate+allopurinol groups and the placebo+allopurinolgroup.

Example 2 Clinical Trial

This study evaluated the efficacy, safety and tolerability ofarhalofenate at 400 mg increasing to 600 mg daily orally in combinationwith febuxostat 80 mg daily orally in gout patients (per criteria of theAmerican Rheumatism Association) with hyperuricemia.

In addition to colchicine 0.6 mg daily for flare prophylaxis, allpatients received febuxostat and arhalofenate in the following orderduring the Treatment Phase:

-   -   Days 1 through 7: febuxostat 80 mg orally once daily (febuxostat        only period)    -   Days 8 through 21: febuxostat 80 mg plus arhalofenate 400 mg        orally once daily (febuxostat plus arhalofenate 400 mg period)    -   Days 22 through 35: febuxostat 80 mg plus arhalofenate 600 mg        orally once daily (febuxostat plus arhalofenate 600 mg period)

The sUA levels were assessed before the start of each dosing period (Day1, Day 8, Day 22) and at the end of the Treatment Phase (Day 36). Serumurate levels were also measured on the last day of each dosing period(Day 7, Day 21, and Day 35) at 4 different time points; pre-dose(fasting), 2 hours post-dose, 6 hours post-dose, and 10 hours post-dose.

Dose/Route/Regimen

-   -   Colchicine: 0.6 mg/oral/daily from Day-16 through Day 49    -   Febuxostat: 80 mg/oral/daily from Day 1 through Day 35    -   Arhalofenate: 400 mg/oral daily from Day 8 through Day 21; 600        mg/oral/daily from Day 22 through Day 35

Duration of Treatment

-   -   Phase 1: Screening Phase: 1 to 4 weeks    -   Phase 2: Run-in/Stabilization Phase: >2 weeks    -   Phase 3: Treatment Phase: 5 weeks    -   Phase 4: Follow-up Phase: 2 weeks

Safety

The interpretation of the safety and tolerability was made based on theassessment of safety parameters evaluated throughout the study,including clinical laboratory tests, 12-lead ECGs, vital signs, physicalexamination, concomitant medication review, and treatment emergent AEs.The reporting of the safety data was descriptive, and included allpatients receiving at least one dose of arhalofenate.

Pharmacodynamics

The effects of each of the febuxostat plus arhalofenate combinationtreatment periods was assessed as the change in sUA from baseline(Day 1) to end of treatment period for the following endpoints:

-   -   The proportion of patients achieving a sUA<6 mg/dL at Day 22 and        Day 36    -   The proportion of patients achieving a sUA<5 mg/dL at Day 22 and        Day 36    -   The proportion of patients achieving a sUA<4 mg/dL at Day 22 and        Day 36    -   The proportion of patients achieving a sUA<3 mg/dL at Day 22 and        Day 36    -   Absolute and percent change in sUA at Day 22 and Day 36

Results:

A total of 12 patients met the final eligibility criteria and took the1st dose of febuxostat 80 mg on Day 1. A total of 11 patientsparticipated in the arhalofenate-febuxostat periods and completed theentire study.

At Day 8, after one week of daily treatment with 80 mg febuxostat, 11patients (100%) reached sUA target of <6 mg/dL, 6 patients (55%) reached<5 mg/dL, and 1 patient (9%) reached <4 mg/dL. At Day 22, after 2 weeksof daily treatment with 80 mg febuxostat plus 400 mg arhalofenate(preceded by 80 mg febuxostat daily for 1 week), statisticallysignificantly higher proportion of patients achieved sUA target of <5mg/dL compared with Day 8 (sUA<5.0 mg/dL in 10 patients, p=0.0455). ByDay 36, after 2 weeks of daily treatment with 80 mg febuxostat plus 600mg arhalofenate (preceded by 80 mg febuxostat daily for 1 week and 80 mgfebuxostat plus 400 mg arhalofenate for 2 weeks), statisticallysignificantly higher proportion of patients achieved sUA targets of <5mg/dL and <4 mg/dL compared with Day 8 (sUA<5.0 mg/dL in 11 patients,p=0.0253; sUA<4.0 mg/dL in 7 patients, p=0.0143).

TABLE 2 Summary of Patients Reaching Target Proportion of PatientsPatients patients reached reached reached P-value target: No target: Yestarget (vs. Day 8) sUA < 6.0 mg/dL 0 11 100.00 sUA < 5.0 mg/dL 5 6 54.55sUA < 4.0 mg/dL 10 1 9.09 sUA < 3.0 mg/dL 11 0 0.00 sUA < 6.0 mg/dL 0 11100.00 . sUA < 5.0 mg/dL 1 10 90.91 0.0455 sUA < 4.0 mg/dL 8 3 27.270.1573 sUA < 3.0 mg/dL 10 1 9.09 0.3173 sUA < 6.0 mg/dL 0 11 100.00 .sUA < 5.0 mg/dL 0 11 100.00 0.0253 sUA < 4.0 mg/dL 4 7 63.64 0.0143 sUA< 3.0 mg/dL 9 2 18.18 0.1573

The mean percent (and absolute) reductions in sUA at Day 8, Day 22 andDay 36 from Day 1 were −47.8% (−4.3 mg/dL), −53.5% (−4.8 mg/dL), and−60.4% (−5.5 mg/dL), respectively. When comparing Day 8, Day 22 or Day36 mean sUA values with Day 1 values, all of the mean absolute changesand mean percent changes in sUA were statistically significant(p<0.0001). At Day 22 and Day 36, the mean percent (and absolute)reductions in sUA from day 8 were −11.0% (−0.5 mg/dL), and −24.4% (−1.1mg/dL), respectively. When comparing Day 22 or Day 36 mean sUA valueswith Day 8 values, all of the mean absolute changes and mean percentchanges in sUA were statistically significant (p<0.0001 for all except,p=0.0001 for percent change at Day 22).

No clinically meaningful differences were observed among the studytreatments in adverse events, clinical laboratory test results, vitalsigns, ECG overall impression, or physical examination results.

While the foregoing description describes specific embodiments, thosewith ordinary skill in the art will appreciate that variousmodifications and alternatives can be developed. Accordingly, theparticular embodiments and examples described above are meant to beillustrative only, and not to limit the scope of the invention, which isto be given the full breadth of the appended claims, and any and allequivalents thereof.

What is claimed is:
 1. A method of lowering the serum uric acid level ofa subject with hyperuricemia, comprising concomitantly administering tothe subject a therapeutically effective amount of a first urate-loweringagent that is (−)-halofenate, or a pharmaceutically acceptable saltthereof, substantially free from its (+)-enantiomer, and a secondurate-lowering agent that is a xanthine oxidase inhibitor which isfebuxostat, where the concomitant administration provides an additive orover-additive lowering of the serum uric acid level of the subject. 2.The method of claim 1, where the first urate-lowering agent is(−)-halofenate.
 3. The method of claim 1 where the first urate-loweringagent is administered at between about 100 mg/day and about 1000 mg/day.4. The method of claim 1, where the febuxostat is administered atbetween about 10 mg/day and about 240 mg/day.
 5. The method of claim 2,where the (−)-halofenate is administered at between about 400 mg/day andabout 800 mg/day and the febuxostat is administered at between about 40mg/day and about 120 mg/day.
 6. The method of claim 5, where the(−)-halofenate is administered at about 400 mg/day, about 500 mg/day,about 600 mg/day, about 700 mg/day, or about 800 mg/day.
 7. A method oflowering the serum uric acid level of a subject with hyperuricemia,comprising concomitantly administering to the subject a therapeuticallyeffective amount of a first urate-lowering agent that is (−)-halofenicacid or a pharmaceutically acceptable salt thereof, substantially freefrom its (+)-enantiomer, and a second urate-lowering agent that is axanthine oxidase inhibitor which is febuxostat, where the concomitantadministration provides an additive or over-additive lowering of theserum uric acid level of the subject.
 8. The method of claim 7, wherethe first urate-lowering agent is (−)-halofenic acid.
 9. The method ofclaim 7 where the first urate-lowering agent is administered at betweenabout 100 mg/day and about 1000 mg/day.
 10. The method of claim 7, wherethe febuxostat is administered at between about 10 mg/day and about 240mg/day.
 11. The method of claim 9, where the (−)-halofenic acid isadministered at about 100 mg/day, about 200 mg/day, about 300 mg/day,about 400 mg/day, about 500 mg/day, about 600 mg/day, about 700 mg/day,about 800 mg/day, about 900 mg/day, or about 1000 mg/day and thexanthine oxidase inhibitor is febuxostat and is administered at betweenabout 40 mg/day and about 120 mg/day.